Reduced Thalamic Excitation to Motor Cortical Pyramidal Tract Neurons in Parkinsonism

Degeneration of midbrain dopaminergic (DA) neurons elevates basal ganglia inhibitory output, leading to reduced motor output from the primary motor cortex (M1) and motor symptoms of Parkinson’s disease (PD). However, M1 circuit adaptations and their roles in PD pathophysiology remain undefined. Using multidisciplinary approaches, we found that DA degeneration induces cell-subtype- and input-specific reduction of thalamic excitation to M1 pyramidal tract (PT) neurons. Physiological and anatomical analyses suggest that DA degeneration induces a loss of thalamocortical synapses to M1 PT neurons, resulting in an impaired thalamic driving of their activities. Moreover, the decreased thalamocortical connectivity are mediated by an excessive activation of NMDA receptors of M1 PT neurons. Further, the decreased thalamocortical transmission in parkinsonism can be rescued by chemogenetically suppressing basal ganglia outputs. Together, our data suggest that the reduced cortical outputs in parkinsonism are not only an immediate consequence of basal ganglia inhibition but also involves specific local circuitry adaptations within M1.Funding Information: This work was supported by the National Institute of Neurological Disorders and Stroke (grant#: R01NS121371). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee at Van Andel Research Institute (reference#: 22-02-006).